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By using HD knock-in mice and cultured cells, we found that the pathogenic form of the HD protein is differentially ubiquitinated via K48 and K63 in ubiquitin. K48-mediated ubiquitination promotes huntingtin (Htt) degradation while K63-mediated ubiquitination accelerates its aggregation. The K-48\u2013mediated ubiquitination depends on Ube3a, whose expression declines in aged brain. Overexpression of Ube3a in old HD KI mouse brain can reduce mutant Htt accumulation and aggregation. The age-dependent decline in Ube3a may contribute to the late-onset neuropathology in HD.<\/jats:p>","DOI":"10.1073\/pnas.1402215111","type":"journal-article","created":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T02:13:03Z","timestamp":1396318383000},"page":"5706-5711","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":126,"title":["Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A"],"prefix":"10.1073","volume":"111","author":[{"given":"Kavita P.","family":"Bhat","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; and"},{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan-En","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; 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